This invention relates to the valproic acid analog 2-n-propyl-4-hexynoic acid, and to its use for the treatment and prevention of migraine and affective illness. The valproic acid analog of the present invention is believed to be an effective anti-migraine and anti-affective illness drug with greatly reduced adverse effects including neurotoxicity and teratogenic potential compared to valproic acid. This invention thus provides an improved method for treating and preventing migraine and affective illness.
Migraine is defined as a periodically occurring vascular headache characterized by pain in the head (usually unilateral), nausea and vomiting, photophobia, phonophobia, vertigo and general weakness. Migraine is the most common type of vascular headache and affects as many as 15% of the world""s population. Of the different types of migraines, classical migraine and common migraine are the two most prevalent. The major difference between the two types of migraines is that classical migraines are preceded by the appearance of neurological symptoms before an attack whereas common migraines are not preceded by such symptoms. Migraine is caused by intermittent brain dysfunction. However, the precise pathophysiological mechanisms involved are not understood. The head pain is believed to involve blood vessel dilation and a reduction in the brain""s pain-relieving chemicals.
Analgesics are often used to treat infrequent and mild migraines. Analgesics reduce the pain of a migraine and in the case of aspirin also discourage clumping of blood platelets. However, for moderate to severe migraines, stronger medications such as ergotamine and valproic acid are necessary. Ergotamine tartrate is a vasoconstrictor which counteracts the painful dilation stage of the headache. When taken during the early stages of an attack, ergotamine tartrate helps to relieve the classic and common migraine symptoms. Valproic acid has been shown to be effective in both the treatment and prevention of migraine, however, its mechanism of anti-migraine action is unclear. It is believed that valproic acid increases brain gamma-aminobutyric acid (GABA) levels and in doing so may activate the GABA receptor and suppresses migraine-related events.
A relationship has been reported between migraine, affective illness and epilepsy. Although the three disorders are distinct, they all are paroxysmal dysregulations of the nervous system that partially overlap in their pharmacology. Some drugs, such as valproic acid, are effective in treating all three syndromes, suggesting the presence of shared underlying pathophysiology, while other drugs are effective for treating one syndrome. For example, beta blockers which are effective against migraine are not useful for treating the other two syndromes and may even exasperate depression.
The kindling model for complex-partial seizures is based on the progressive development of seizures combined with electroencephalographic (EEG) paroxysmal patterns induced by repeated initially subconvulsive electrical stimulation of limbic structures, e.g. the basolateral nucleus of the amygdala. Once established, the phenomenon persists for months. Since the amygdala kindled seizures in animals share numerous characteristics with complex-partial seizures in humans, it is presently the best animal model of complex partial seizures (Goddard et al. 1969; Loscher and Schmidt 1988; Lxc3x6scher 1993). One major advantage of using the amygdala kindling model is that both behavioral and EEG parameters of the partial and generalized seizures can be measured. Furthermore, the amygdala kindling model is reported to be appropriate for studying diseases such as migraine, affective illness and epilepsy which increase in severity overtime and in a manner which is related to the number of symptomatic episodes.
Previously, the valproic acid analog 2-n-propyl-4-hexynoic acid was shown to be an improved antiepileptic compared to valproic acid by the subcutaneous pentetrazole convulsion test (PTZ test). Experimental findings from various studies in which both the PTZ test and the amygdala kindling test were employed indicate that drugs that are effective against the PTZ induced seizures are not necessarily effective against amygadala kindled seizures and vice versa (Loscher, W., and Honack, Dagmar., Eur.J. Pharmacol. (1993), 232:147-158; Johnson, D. et al., Epilepsy Res. (1991), 8:64-70). Therefore, not all anticonvulsant are effective against amygdala kindled seizures. In other words, drugs that are antiepileptics are not necessarily effective in the treatment of migraine or affective illness.
Recent publications suggest that the amygdala kindling model is appropriate for studying shared mechanisms underlying the increase in severity over time of symptomatic episodes in epilepsy, migraine and affective illness (R. Post and S. Silberstein, Neurology (1994), 44: S37-S47; R. Post and S. Weiss, Molecular Neurobiology (1996), 13:33-60). In amygdala kindling, intermittent electrical stimulation of the amygdala of the brain is first without effect, but eventually following repeated stimulation, results in increasing biochemical and physiological responses cumulating in a full-blown convulsion. Following continued triggering of seizures, seizures begin to emerge spontaneously. This progression of symptom severity involves a long-lasting change in the property of the neuron. Experimental findings indicate that kindling induced in animals shares many features with human affective illness, migraine and epilepsy, such as progression from triggered to spontaneous, changes in behavior patterns during the seizure and responsiveness to certain anti-seizure drugs. Therefore, amygdala kindling may serve as a model to study the possible underlying mechanisms for the memory-like processes that may be involved in migraine, affective illness and epilepsy.
U.S. Pat. No. 4,942,182 reports the stage dependent sensitivity to drug treatment of seizures induced by amygdala kindling. In this model, carbamazepine suppresses complete amygdala-kindled seizures in rats, but is ineffective in preventing their development. Diazepam however, which is effective in inhibiting the earlier stages of seizure development is not effective during the late stages when seizures occur spontaneously. Phenytoin, another anticonvulsant drug has activity opposite that of diazepam being an effective block of spontaneous seizures, but not seizures elicited during the early stages of kindling.
The amygdala kindling model is also an important model to evaluate potentially useful drugs because it can provide information different from that of other seizure models. For example, whereas carbamazepine is an effective anti-convulsant in several seizure models including the amygdala kindling model, it is less effective on seizures induced by pentylenetetrazole and high dose picrotoxin.
Valproic acid is an effective drug for the treatment and prevention of epilepsy, migraine and affective illness. However, it has a short duration of action, and suffers from serious side effects such as sedation, potentially fatal hepatotoxicity and tertogenicity. There has been a considerable effort to discover analogs of valproic acid that are equally effective, but have a longer duration of activity and a greater margin of safety. One study has demonstrated that the valproic acid analog 2-n-propyl-4-hexynoic acid is an effective antiepileptic with a longer duration of activity and greatly reduced sedative and teratogenic effects compared to valproic acid (Nau et al, U.S. application Ser. No. 08/344,810, which is hereby incorporated in its entirety by reference). The compound 2-n-propyl-4-hexynoic acid is therefore an improved antiepileptic. However, since the compound was only examined in the subcutaneous pentetrazole convulsion test (PTZ test) which is designed to evaluate the effectiveness of drugs against epilepsy, the effectiveness of the compound for the treatment of migraine or affective illness is not known.
This invention relates to the compound 2-n-propyl-4-hexynoic acid, pharmaceutical compositions containing this compound, and their use to treat and/or prevent migraine and affective illness. The compound for use in this invention is believed to be effective in the treatment and prevention of migraine and affective illness, and exhibits greatly reduced adverse effects and longer duration of activity, when compared to valproic acid.
One object of this invention is to provide a method for treating and/or preventing migraine and affective illness (including unipolar, bipolar illness and acute mania) due to a variety of causes, by administering to an individual in need of such treatment a therapeutically or prophylactically effective amount of 2-n-propyl-4-hexynoic acid.
Another object of this invention is to provide pharmaceutical compositions for the treatment and/or prevention of migraine and affective illness that has longer duration of activity, exhibits lower adverse effects, and avoids teratogenic toxicity compared to valproic acid.